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J Biol Chem, Vol. 274, Issue 19, 13193-13197, May 7, 1999
From the Department of Medicine and the Committee on Cancer
Biology, The University of Chicago, Chicago, Illinois 60637
The cAMP-dependent protein kinase
(PKA) exhibits both inhibitory and stimulatory effects upon growth
factor signaling mediated by the mitogen-activated protein kinase
signaling pathway. PKA has been demonstrated to inhibit Raf-1-mediated
cellular proliferation. PKA can both prevent Ras-dependent
Raf-1 activation and directly inhibit Raf-1 catalytic activity. In
contrast to the inhibitory effect of PKA on Raf-1-dependent
processes, PKA potentiates nerve growth factor-stimulated PC12 cell
differentiation, a B-Raf mediated process. This potentiation, rather
than inhibition, of PC12 cell differentiation is curious in light of
the ability of PKA to inhibit Raf-1 catalytic activity. The kinase
domains of Raf-1 and B-Raf are highly conserved, and it has been
predicted that B-Raf catalytic activity would also be inhibited by PKA.
In this study we examined the ability of PKA to regulate the kinase
activity of the B-raf proto-oncogene. We report that nerve
growth factor-stimulated B-Raf activity is not inhibited by PKA. By
contrast, an N-terminally truncated, constitutively active form of
B-Raf is inhibited by PKA both in vitro and in transfected
PC12 cells. These results suggest that the N-terminal regulatory domain
interferes with the ability of PKA to modulate B-Raf catalytic activity
and provide an explanation for the observed resistance of
B-Raf-dependent processes to PKA inhibition.
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